A fruitful century for the scalable synthesis and reactions of biphenyl derivatives: applications and biological aspects

This review provides recent developments in the current status and latest synthetic methodologies of biphenyl derivatives. Furthermore, this review investigates detailed discussions of several metalated chemical reactions related to biphenyl scaffolds such as Wurtz–Fittig, Ullmann, Bennett–Turner, Negishi, Kumada, Stille, Suzuki–Miyaura, Friedel–Crafts, cyanation, amination, and various electrophilic substitution reactions supported by their mechanistic pathways. Furthermore, the preconditions required for the existence of axial chirality in biaryl compounds are discussed. Furthermore, atropisomerism as a type of axial chirality in biphenyl molecules is discussed. Additionally, this review covers a wide range of biological and medicinal applications of the synthesized compounds involving patented approaches in the last decade corresponding to investigating the crucial role of the biphenyl structures in APIs.


Introduction and scope
For many decades, biphenyl compounds and their isosteres have been considered a fundamental backbone in synthetic organic chemistry and natural products due to their omnipresence in medicinally active compounds, marketed drugs and natural products. For example, there are various biologically active natural products that contain biaryl scaffolds (vancomycin, 1,2 WS 43708A 3 and Arylomycin A 4 ) (Fig. 1).
Since biphenyls are neutral molecules without a functional group, functionalization is required for them to react. Biphenyls consist of two benzene rings linked at the [1,1′] position. The reactions of biphenyls are similar to benzene as they both undergo electrophilic substitution reaction. Biphenyl derivatives which are used to produce an extensive range of drugs, products for agriculture, uorescent layers in organic lightemitting diodes (OLEDs) 5,6 and building blocks for basic liquid crystals are signicant intermediates in organic chemistry besides being the structural moiety of an extensive range of compounds with pharmacological activities. [7][8][9][10] Whereas several biphenyl derivatives serve as versatile and multifaceted platforms in medicinal chemistry, as large number of biphenyl derivatives are patented and broadly used in medicine as the antiandrogenic, 11 immunosuppressant, antifungal, antibacterial, antimicrobial, anti-inammatory, anti-proliferative, osteoporosis, antihypertensive, antitumor, b-glucuronidase inhibition activity, anti-leukemia agent hypotensive, anticholinesterase, anti-diabetic and antimalaria drugs. 12 In addition, 6-(3-(adamantan-1-yl)-4-methoxyphenyl)-2-naphthoic acid which trademark drug (adapalene) as a third-generation topical retinoid primarily used for treating acne vulgaris, anti-inammatory, antibacterial. 13 Another example is sonidegib which acts as a drug for basal cell carcinoma. 14 Additionally, other manufactured naturally occurring chemicals, including the biphenyl nucleus, have shown noteworthy biological activities, such as the antipyretic properties of fenbufen 15 and urbiprofen and their role as non-steroidal anti-inammatory drugs (NSAIDs) (Fig. 2). 16

Synthesis of biphenyl systems
Wurtz reported the rst trial for carbon-carbon bond formation reactions between two alkyl halides in the presence of sodium metal. Then, Fitting expanded this work to include the C(sp 2 )-C(sp 2 ) homodimerization of aryl halides. Whereby, Ullmann described the Cu-catalyzed homocoupling reaction involving halo-arenes in 1901. In 1914, Bennett and Turner demonstrated the homodimerization of Grignard reagent and phenyl magnesium bromide which promoted by chromium(III) chloride (CrCl 3 ) or anhydrous cupric chloride (CuCl 2 ). 17 Kumada depicted the reaction of aryl halides with arylmagnesium halide or organozinc in the presence of transition metal catalysts. [18][19][20] Whereas, Hiyama produced biaryls via coupling the readily available organosilanes with organohalides. 21,22 In the same context, Negishi et al. 23 reported a regio-and chemoselective method for biaryl synthesis. 24,25 In 1986, a new methodology for cross coupling reaction of organic electrophiles with organostannanes was discovered by Stille. 26,27 Aer that, Suzuki-Miyaura cross coupling became one of the most effective and widely used ways for forming carbon-carbon bonds. 15,28,29 As biphenyl scaffolds are a key step to produce bioactive molecules

Ullmann reaction
The Ullmann reaction was known since 1901, 35 as it has attracted the attention of many chemists trying to synthesize chiral substituted biphenyl. Moreover, the Ullmann reaction usually is achieved at lower temperatures and shorter time frame through coupling the aryl halide 1 in the presence of powdered copper or nickel catalysts, but it has changed in  recent years. 36,37 It is worth mentioning that, the degree of stability of substituted chiral biphenyl depends on the nature of the ortho substituents when this asymmetric Ullman coupling. 38 Whereas, enantioselective biphenyls 2 were obtained via the reaction of ortho-chlorinated benzaldehyde derivatives 1 in the presence of Ni catalyst (Scheme 2). 39

Bennett-Turner
In 1914, the coupling reaction was investigated by Bennett-Turner 40 who reported the synthesis of biphenyl compound 2 via homocoupling reaction of phenylmagnesium bromide (3) and CrCl 3 in diethyl ether (Et 2 O), incidental to an attempt to prepare organochromium compound. 41 Bennett-Turner reaction can be achieved by using CuCl 2 . 42 In this context, noteworthy is the contribution of Krizewsky with Turner using a CuCl 2 promoted homocoupling reaction instead of CrCl 3 (Scheme 3). 17,42,43 Ultimately, treatment of the tetrauoro-3-methoxybenzene (4) with CuCl 2 and lithium tert-butoxide (t-BuOLi) in the presence of O 2 gas produced a mixture of biphenyl coupling product 5 (56%) and the corresponding phenol 6 (38%). The proposed mechanism involves in situ deprotonation with oxidative dimerization has been studied by Do et al. 44 The production of corresponding phenol was reasonable through trapping of the formed aryl lithium with oxygen gave rise to an aryl anion species which was less prone to oxygenation and more likely to form a copper adduct that would undergo oxidative coupling reaction (Scheme 4).
In 2003, Demir and coworkers reported using of low-cost copper salts (Cu(I) and Cu(II)) as they are able to mediate the dimerization of arylboronic acids 7 to afford the corresponding symmetrical substituted biaryl 2 in good yields. The reaction can be possibly catalyzed under an oxygen atmosphere without a signicant loss of yields. 45 In 2009, Kirai et al. 46 improved the previous protocol for oxidative dimerization which relying on catalysts that would facilitate transmetalation. As they reported a new effective methodology for homocoupling of aryl boronic acid derivatives 7 under stirring conditions through using the catalytic amount of [{(phen)Cu(m-OH)} 2 Cl 2 ]$3H 2 O. It is worthy to mention that the homocoupling reaction proceeds without any additives such as oxidant or base. Besides, this method tolerates different substituents on the arylboronic acids such as nitro group, halogens and carbonyls (Scheme 5).
The formation of symmetrical substituted biaryl 2 is explained according to the following postulated mechanism: the reaction proceeds by the hydroxido ligand attacks the oxophilic boron center, followed by transmetalation of arylboronic acids 7 with (m-hydroxido)copper(II) complex 2A to yield bimetallic arylcopper(II) intermediate 2B without using any base. Biaryl products 2 afford through the concomitant one-electron reduction of each copper center [2LCu II -Ar / 2LCu I + Ar-Ar]. As the binuclear copper models efficiently activate molecular oxygen, in the same time the molecular oxygen smoothly bind to the resulting bimetallic intermediate [{(phen)Cu I (m-Cl)} 2 ] 2C, which is reoxidized to afford (m-hydroxido)copper(II) complex 2A (Scheme 6). The present binuclear O 2 activation and binuclear reductive elimination mechanism is quite different from that proposed for palladium-catalyzed aerobic homocoupling. 46

Kumada cross coupling
Since 1972, Kumada catalyzed cross coupling reaction of organozinc or organomagnesium with arylhalide in the presence of Pd, Ni, Cu, Fe or Co catalyst. [18][19][20] However, this reaction was limited with Pd catalyst compared to Ni catalyst due to the high reactivity of organomagnesium, 47 as well as less toxicity and non-expensive Ni catalyst. 48 Besides, arylchlorides were preferable than aryliodides and arylbromides because of low price. Treatment of chloromethylbenzene 8 with (methoxyphenyl) magnesium bromide 9 in the presence of Ni complex and THF afforded 4′-methoxy-2-methyl-biphenyl 10 in (87%) yield. 49 Whereas, in the presence of Pd catalyst, product 10 produced in (94%) yield (Scheme 7). 50 Recent research has largely been focused on directed C-H activation. Primary imines 12 produced by a Grignard reagent's nucleophilic addition to nitrile group 11 which is susceptible to attack make it easier to introduce copper(II) into a close C-H bond. Primary imine derivatives 12 underwent a closure under oxygen-mediated elimination affording the respective phenanthridine derivatives 13 (Scheme 8). 51,52 The proposed mechanism for the synthesis of the phenanthridine derivatives 13 is illustrated in Scheme 9. This involves the nucleophilic addition of biaryl-2-carbonitriles 11 and Grignard reagents to produce N-H imines 12, followed by their Cu-catalyzed C-N bond led to formation of the aromatic C-H bond, in which molecular oxygen is a necessary component to complete the catalytic process (Scheme 9). 51,52

Hiyama cross-coupling
One of the most important corn stone for synthesizing biaryl is Hiyama cross-coupling due to the distinctive features of organosilane reagent such as less reactivity, availability, nontoxicity, high sustainability and cheap, in addition to its ability to functionalize stereo and regioselective compounds. [53][54][55] Rhodium-catalyzed o-C-H arylation reaction of arylsilane 14 with ethyl benzimidate 15 with in the presence of pentamethylcyclopentadienyl rhodium dichloride dimer [Cp*RhCl 2 ] 2 , silver hexauoroantimonate(v) (AgSbF 6 ), silver oxide (Ag 2 O) and TBAF produced biphenyl-2-carbonitrile derivative 16. 56 Whereby, reuxing a mixture of arylsilane 14 with arylhalide 1 in a mixture of AcOH and toluene, Pd catalyst, and tetrabutylammonium uoride (TBAF) as a base afforded biphenyl 2. Furthermore, this method was applied under mild condition and tolerated high functional groups (Scheme 10). [57][58][59] Noor and coworkers 57 suggested the proposed mechanism for Hiyama cross coupling. Analogous to other metal catalyzed cross coupling mechanism, Hiyama cross coupling passed through three steps. The oxidative addition of aryl halide to palladium metal leaded to the conversion of Pd(0) to Pd(ii). Then, transmetallation step occurred in the presence of base such as (KF, n-Bu 4 NF) which encouraged the C-Si bond to split and establish a new C-Pd bond. 53,60 Finally, in the reductive elimination step a new C-C bond was formed and Pd returned back to the oxidation state (0) (Scheme 11). 24

Suzuki-Miyaura cross-coupling
In the last decade, Suzuki-Miyaura coupling reaction (SMC) has witnessed an increase interest due to its widespread academic and industrial application in the production of ne chemicals, polymers, materials, and pharmaceuticals. 61 SMC reaction is also used to tag DNA with luminous intercalator substituents for DNA sequencing and diagnostics. 62 In 1979, Akira Suzuki, Norio Miyaura and Kinji Yamada reported SMC which is the most common method in the formation of carbon-carbon bond in drug discovery. 28,29 In the context, the reaction of various aryl bromide derivatives 1 with commercially available aryl boronic acids 7 under action of palladium-catalyzed Suzuki coupling reaction on porous carbon nanospheres (Pd/CNS) afforded biphenyl derivatives 2. It is worthy to mention that, using (Pd/ CNS) as catalyst is preferable than other Pd salts due to its highly effective, and lower cost (Scheme 12). 63 The simple mechanism for (SMC) reaction passed through three steps. 23,64 The rst step is the oxidative addition in which organo palladium(II) complex 2A is formed via coupling of aryl halide 1 with palladium catalyst and this is happening via breaking carbon-halogen bond and by squeezing palladium between the aryl and halogen group. The second step is the transmetalation whereas organoboron compound is converted to nucleophilic borate in the presence of base such as sodium tert-butoxide and carbonate salts then attacking on a Pd(II) complex 2B to form 2C complex. Finally, reductive elimination step in which the two aryl groups are reductively eliminated from Pd(II) complex 2C and combine together to form C-C bond and the palladium is reformed (Scheme 13). 65,66 Biphenyl phosphine was effective ligand in metal catalyzed reaction as hydroformylation, asymmetric hydrogenation and allylic alkylation. Reaction of equimolar amount of (2-bromophenyl)diphenylphosphine oxide ((2-BrC 6 H 4 )OPPh 2 ) 17 with aryl boronic acids 7 in the presence of bis(dibenzylideneacetone)palladium catalyst (Pd(dba) 2 ), triphenylphosphine (PPh 3 ) (4 equiv.) and potassium phosphate (K 3 PO 4 ) (2 equiv.) as a base in reuxing dioxane at 105°C yielded biphenyl phosphine oxide derivatives 18 followed by reduction with a mixture of trichlorosilane and catalytic drops of triethylamine (TEA) produced biphenyl phosphine derivatives 19 (Scheme 14). 67 Substituted biphenyl anilines play a vital role in the synthesis of pharmaceutical, dyes, organometallic complexes and ferromagnetic materials due to the ability of amino group to react with aldehyde and ketone to produce Schiff products with strong electronic donor and versatile frameworks. 68 Furthermore, treatment of 4-chloroaniline (20) with uorinated phenyl boronic acid 7 in reuxing a mixture of toluene and water with a catalytic amount of palladium acetate (Pd(OAc) 2 ) and bulky phosphine ligand (SPhos) yielded uorinated aminobiphenyl derivatives 21. 69 Analogously, reuxing of 4-chloroaniline (20) with uorinated phenyl boronic acid 7 with DMF in the presence of catalytic Pd(OAc) 2 and K 3 PO 4 as a base at 80°C afforded uorinated aminobiphenyl derivatives 21 (Scheme 15). 68 Fluorinated biphenyls are scaffolds for various applications due to their rigidity, chemical stability and electron poor nature. Furthermore, uorinated biphenyls are used to develop OLEDs, liquid crystal displays (LCDs), organic semiconductors, metalorganic frameworks (MOF), and organic polymer of intrinsic microporosity (OMIMs). In addition, organoourine as substituents of biphenyl have become widespread drug motifs, as they affect nearly adsorption, metabolism, distribution and excretion properties of lead compounds. 70 Buleld et al. 71  with triuoroboronic acid 7 in the presence of sodium carbonate (Na 2 CO 3 ) as a base and tris(dibenzylideneacetone)dipalladium(0) (Pd 2 (dba) 3 ) as a catalyst with SPhos as a ligand in reuxing with a mixture of THF, toluene, and H 2 O. Whereas, using XPhos as a ligand and potassium carbonate (K 2 CO 3 ) as base afforded uorinated biphenyl 22 only with an excellent yield (99%) (Scheme 16). The reactivity of aryl halides is dependent on the dissociation energy of the C-X bond according to (I > Br > Cl > F). As a larger halogen atom will be a better leaving group due to having a lower bond dissociation, thus increasing the reactivity. As a result of aforementioned information, boronic derivative 7 couples with iodide atom faster than uorine atom (Scheme 16). 72 Whereby, reaction of aryl halide 1 with various uorinated boronic acids 7 in the presence of palladium catalyst complex and K 3 PO 4 as a base in a reuxing solvent mixture of tetrahydrofuran (THF) and water furnished uorinated biphenyl 24. 6 Additionally, uorinated biphenyl 26 was synthesized by reuxing iodobenzene 1 and arylboronate 25 in Cu catalyst, phenanthroline ligand (phen) and DMF (Scheme 17). 73 Palladium catalyst was predominantly used in Suzuki coupling reaction, but due to its scarcity and high price, it was replaced by Ni and Co catalyst. Cobalt salts have stronger catalytic activity and a reduced tendency to yield homocoupling by-products. However, iron was considered the best substitute for a Pd catalyst because it was the least toxic and the most abundant transition metal. 74 Biphenylpyrrole derivative 29 was obtained via the reaction of arylhalide 28 with lithium arylboronates 27 in the presence of Fe catalyst and 1,3-bis(trimethylphenyl)-1,3-dihydro-2H-imidazol-2-ylidene (IMes) as a ligand. 75 Whereas, the reaction of chloromethylbenzene 30 with 27 in the presence of cobalt(II) chloride (CoCl 2 ) and a ligand/precursor named bis(2,6-diisopropylphenyl)-1Himidazol-3-ium afforded methylbiphenyl 31 (Scheme 18). 76 The suggested mechanism involved the formation of a lowvalent molecular iron complex that engages in the reversible coordination of both bromide and the pyrrole-containing substrate 28. The C-Cl bond in 28 is reductively activated by the resulting ferrate complex. The biphenylpyrrole product 29 was delivered by reductive elimination, and the active catalyst was renewed by bromide abstraction (Scheme 19). 75 Additionally, nickel catalyzed Suzuki coupling reaction of chlorobenzene derivative 1 with substituted phenylboronic acid 7 in the presence of Ni catalyst, ferrocenylmethylphosphines derivative as a ligand, K 3 PO 4 and THF afforded biphenyl derivative 2 (Scheme 20). 77 Biphenyl tyrosine derivatives are biologically active molecules including arylomycin A 2 act as an antibacterial drug. Tyrosine derivatives were keys for the synthesis of biaryl derivatives via SMC reaction. Nevertheless, tyrosine compounds must be protected in order to react. 3-Iodo tyrosine (32) was esteried using methanol (MeOH) with thionyl chloride (SOCl 2 ) to afford 2-amino-3-iodophenyl-propanoate 33. Then, the amino group was protected using tert-butyloxycarbonyl (t-Boc) and sodium bicarbonate (NaHCO 3 ) in MeOH to furnish N-tertbutyloxycarbonyl-3-iodotyrosine methyl ester (34). Reuxing Ntert-butyloxycarbonyl-3-iodotyrosine ester 34 in the presence of Pd(OAc) 2 , K 2 CO 3 and hetero aryl triuoroborate salt 35 in MeOH to afford t-butoxycarbonyl-(6-hydroxy-[biphenyl]-yl) propanoate derivatives 36. Finally, deprotection of compounds 36 was achieved via heating them with dil. HCl at 70°C for 3 h to give the free amino acid 37 (Scheme 21). 4 Burmaoglu et al. 78 synthesized new biphenyl chalcone derivatives 42 according to the reaction sequences. First, preparation of 3-bromo-2,4,6-trimethoxyacetophenone (39) through bromination reaction of 2,4,6-trimethoxy acetophenone (38)  with ceric ammonium nitrate (CAN) and lithium bromide (LiBr) in acetonitrile (CH 3 CN), followed by applying SMC of compound 39 with phenylboronic acid (7) in the presence of Pd(PPh 3 ) 4 and K 2 CO 3 in a mixture of ethanol (EtOH) and toluene afforded 2,4,6-trimethoxy-[1,1′-biphenyl]ethan-1-one 40 (Scheme 22). Claisen-Schmidt condensation reaction of substituted biphenyl 40 and benzaldehydes 41 yielded biphenyl chalcone derivatives 42 (Scheme 22). Consequently, biphenyl-substituted chalcone scaffolds which are classied as privileged metabolic enzyme inhibitor motifs which essential support in the treatment of Alzheimer's disease (AD) and glaucoma due to hydrophobic effect and their ability to bind with multiple receptors.

Scheme 19
The suggested mechanism for biphenylpyrrole synthesis.
Scheme 20 Synthesis of biphenyl derivatives 2 via nickel catalyzed SMC.

Scheme 26
The proposed mechanism for the formation of polycyclic product 52.
produced by reuxing zinc powder and calcium chloride (CaCl 2 ) with compound (R)-65 in EtOH. Aer that, hypophosphorous acid (H 3 PO 2 ) was added to compound (R)-66 in a mixture of THF and H 2 O, followed by treatment with cupper(i)oxide, and sodium nitrite ( was obtained in two steps involving adding n-butyl lithium dropwise to compound (R)-67 in a mixture of THF and hexane as rst step. In the second step, chlorodicyclohexylphosphane (Cy 2 PCl) was added with stirring to replace bromide by dicyclohexylphosphane group (Scheme 28). 88 The synthesis of biphenyl oxazole derivatives 70 was reported by Ahmad et al. 89 under mild conditions which were enzyme inhibitors and estimated as therapeutic seeds for ailments associated with NPP1 and NPP3 isozymes via Suzuki-Miyaura cross coupling of bromo-phenyloxazole 69 with various boronic acids 7 in a mixture solvent system (toluene/water) (Scheme 29).

Stille cross coupling
Stille cross coupling reaction is one-step coupling reaction for nucleosides synthesis was rst reported in 1986. 26, 91 Stille cross coupling is still a signicant reaction to form C-C bond, and one of the most selective and general methods for palladium catalyzed cross coupling reaction. Therefore, it was constituted to produce a various ring system bearing functional groups and to synthesize several alkenes, alkenyls, oligoarylenes and biaryls. [92][93][94] The interesting advantage of Stille reaction is the using of organotin compounds which are mild reagents and tolerate numerous of functional groups. On the other hand, the only drawback is the water insoluble tin reagents and toxicity of the hydrophobic. 92 Stille cross coupling reaction of aryl halide 1 with triphenyl tin chloride (Ph 3 SnCl) (78) in the presence of catalytic amount of palladium graed on natural asphalt sulfonate Na[Pd-NAS], cesium carbonate (Cs 2 CO 3 ) as a base in reuxing ethanol furnished biphenyl derivatives 2 (Scheme 31). 88,95 In 1986, Chemie John K. Stille described the possible mechanism for Stille cross coupling reaction. Stille cross coupling mechanism passed through three steps: oxidative addition, transmetalation and reductive elimination. In oxidative addition step, the catalytic species Pd(0)Ln is reacted with aryl halide 1 to form Pd(II) complex 2A. In transmetalation step, Pd(II) complex 2A cleavage the C-Sn bond of organotin reagent 78 to produce complex 2B. Finally, reductive elimination step for forming C-C bond and the catalyst is regenerated at the same time (Scheme 32). 96

Negishi cross coupling
Negishi cross coupling reaction among the most important in organic chemistry for forming C-C bond between electrophiles with organozinc reagents and organic halides. Negishi reported an easy regio-and chemoselective method for the synthesis of unsymmetrical biaryl using an aryl-aryl coupling process that is catalyzed by nickel salts. 25 Mechanism of Negishi cross coupling reaction passed through three steps. Initially, an organohalide or pseudohalide (such as triate) is oxidatively added to a low valent metal complex to produce an organometallic derivative with a higher formal oxidation state on the metal center. Then, producing diorganometal species is processed, whereby, the nucleophilic carbon is transmetalate from the nucleophile to the transition metal complex. Finally, a new C-C bond is formed by further reductive elimination, which reproduces the catalytically active species (Scheme 34). 99 metals earth (Ae) such as K, Cs or Rb with benzene afforded C 6 H 5 c − salts and radical coupling to (biphenyl) 2− companied with emission of H 2 gas. Similarly, the direct dehydrogenative coupling of benzene through low-valent alkaline-earth metals (Ae) intermediates was achieved via formation of metal (Ae) complex with a C 6 H 5 2− dianion which acts as reducing agent to bulky b-diketiminate ligand BDI 80A to yield [( DIPeP BDI)Ca] 2 (biphenyl) 81 as dianionic N,C-chelating ligand, which rapidly decomposed to afford biphenyl scaffold 2 (Scheme 35). 100

Rection of biphenyl with diazonium salt
Manchoju et al. 150 emphasized that several tetronic acid derivatives displayed a wide range of pharmacological activities, including acaricidal, insecticidal, HIV-I protease inhibitory, Scheme 52 Acetoxylation of biphenyl with various acids.
Scheme 53 Reaction of biphenyl with diazonium salts.

Nitration of biphenyl
Several reagents could be used to perform the nitration of aromatic compounds. The nitro aromatic compounds are extensively used in the manufacture of perfumes, pharmaceuticals, explosives, plastics, and dyes. Nitration of biphenyl (2) gave various oriented nitrated products 138 and 139 depending upon the nature of conditions and reagents applied on the reaction, as the nitration of biphenyl (2) was employed by reuxing NaNO 3 with SO 3 H-functionalized magnetic core/shell nano catalyst in DCM furnished 4-nitro-1,1′-biphenyl (138). 154 While, treatment of a biphenyl with nitric acid (HNO 3 ) in CCl 4 solvent afforded 2-nitro-biphenyl 139 (Scheme 56). 155

Rection of biphenyl with sulfonanilide derivatives
The development of new methods for C-N bond synthesis is of great importance due to the prevalence nitrogenous compounds in numerous synthetic intermediates, natural products, pharmaceutical agents, and biologically active molecules. Sulfonanilides are a crucial class of synthetic scaffolds used in organic synthesis due to their potent electron-withdrawing effect of the connected sulfonyl group, in addition to, sulfonanilides have a special reactivity toward hypervalent iodine(III). Biphenyl sulfonanilide derivatives 149 were produced in wide range yields (33-87%) by adding meta-chloroperbenzoic acid (mCPBA) to a stirred solution of sulfonamide derivatives 148, biphenyl 2, and iodobenzene (PhI) in a mixture of hexauoroisopropanol (HFIP) and DCM (Scheme 59). 158

Amination reaction
Primary aromatic amines are important building blocks for the formation of biologically active pharmaceutical and agrochemical chemicals, as well as organic functional materials like dyes and pigments. Electrochemical oxidation of biphenyl (2) in a solution of tetrabutylammonium tetrauoroborate (Bu 4 NBF 4 ) and a mixture of CH 3 CN and pyridine followed by adding piperidine afforded aminobiphenyl 150 (Scheme 60). 159 Analogously, under an oxygen atmosphere conditions, the reaction of ammonium carbamate (H 2 NCO 2 − H 4 N + ) as a nucleophile with biphenyl (2) as the arene coupling partner in the presence of a catalytic amount of mesityl acridinium salt, 2,2,6,6tetramethylpiperidine-1-oxyl (TEMPO), and a mixture of DCE and H 2 O afforded para and ortho aminobiphenyl products 150 and 151 respectively (Scheme 60). 160 A proposed mechanism for 4-aminobiphenyl (150) synthesis involves the nucleophilic attack of pyridine on biphenyl (2), followed by one-electron oxidation to produce the intermediate ion 150A which is underwent aromatization process to yield N-arylpyridinium ion intermediate 150B. Then, piperidine is added to the 2-position of the N-arylpyridinium ion 150B, accompanied by ring opening and imine hydrolysis (Scheme 61). 159 On the other hand, the proposed mechanism for the formation of aminobiphenyl 150 involves photoinduced electron transfer (PET) of biphenyl 2 in the presence of acridinium salt as a catalyst to an excited state photoredox radical (cat*) and biphenyl cation radical 150A, which reacted with amine derivatives to yield distonic cation radical 150B. Then, the deprotonation reaction of 150B furnished the radical intermediate 150C, which led to production of aminobiphenyl 150 by oxidative aromatization (Scheme 62). 160

Reaction of biphenyl with bis(pinacol)diborane
The borylation reaction of biphenyl (2) with B 2 pin 2 74 in the presence of potassium t-butoxide (t-BuOK) and (1,5-cyclooctadiene) (methoxy)iridium(I) dimer ([Ir(OMe)COD] 2 ) catalyst in THF with dimethylbipyridyl (dmbpy) afforded tetrakis(Bpin) biphenyl 154. 162 On the other hand, reuxing of biphenyl 2 with B 2 pin 2 74 and a catalytic amount of N-heterocyclic carbene platinum(0) complex (IPr*Pt(dvtms)) gave two different oriented products namely, meta-(Bpin)biphenyl (155) and para-(Bpin) biphenyl (156) (Scheme 64). According to the proposed mechanism supporting the photochemical arene C-H functionalization method. Sulfonium salt 159A is produced by site-selective addition of heteroaromatic sulfoxides 160 to unfunctionalized biphenyl 2 via interrupted Pummerer reactivity. The sulfonium salt 159A label's electron-decient heteroaromatic system can form photoactive electron donor-acceptor (EDA) complexes with triaryl amine donors. Blue-light irradiation of the EDA complex causes single-electron transfer (SET) from the amine donor to salt 159A, which forms the radical cation of the electron donor and stimulates the synthesis of the aryl radical 159B. The radical trap 159B intercepting the aryl radical intermediate produces open shell species 159C, which are prone to oxidation to yield cations 159D, then the active electron-donor catalyst is regenerated. Finally, fragmentation of either tert-butyl isocyanide Scheme 66 Construction of biphenyl nitrile derivative.

Scheme 67
The postulated mechanism for biphenyl carbonitrile synthesis. cation from 159D yields the required C-H functionalization products 159 (Scheme 67). 165 The proposed mechanism for phenylbenzonitrile synthesis 159 starts with photo irradiation of acridinium catalyst to its oxidizing excited state Mes-Ac + *, followed by oxidation of biphenyl 2 to its radical cation 2A to produce the reduced acridinium Mes-Ac radical. Then, cyanide engages with 2A at ortho or para position. According to Fukuzumi cyclohexadienyl radical (2B) undergoes oxidation using molecular oxygen to give phenylbenzonitrile 159. Finally, molecular oxygen or hydroperoxy radical oxidizes Mes-Ac radical to reproduce the catalyst (Scheme 68). 166

Reaction of biphenyl with sulfonium salt
Several methods reported for the introduction of SCF 3 group into biphenyl derivative, for example stirring of sodium tri-uoromethanesulnate (CF 3 SO 2 Na) with biphenyl derivative 2 in triuoromethanesulfonic anhydride (Tf 2 O) and DCM at ambient conditions furnished [1,1′-biphenyl]-4yl(triuoromethyl)sulfane derivatives 161 in range yields (65-82%) (Scheme 69). 167 The proposed mechanism for the synthesis of [1,1′biphenyl]-4-yl(triuoromethyl)sulfane 161 starts with the promotion of triuoromethylthiolation using Tf 2 O and CF 3 -SO 2 Na to afford an intermediate sulfonate sulnate anhydride through self-disproportionation. Two possible routes lead to the nal product. In path I, half of sulfonate sulnate anhydride intermediate was oxidized to form TfO-SO 2 CF 3 and another part is reduced to form CF 3 SOSO 2 CF 3 . Finally, the transfer of tri-uoromethylthiolation from CF 3 SOSO 2 CF 3 to biphenyl (2) to afford SCF 3 product 161 (Scheme 70).

Biphenyl atropisomerism
As reected in the last few years, the crest of a sizable wave in the development of new ligands in drug discovery and medicinal chemistry, the recent literature addressing atropisomerism has been hard to miss, as biphenyl atropisomers have received considerable attention as chiral building blocks for chiral catalysts in asymmetric syntheses eld. The rst experimentally described molecule with atropisomerism phenomenon was 6,6′dinitro-2,2′-diphenic acid by Christie and Kenner in 1922. 174,175 As the inclusion of the biphenyl isosteres represent 4.3% of all known drugs. 176 Atropisomerism is dened as stereochemistry arising from highly hindered bond rotation that creates a chiral axis. The rotational barrier of an atropisomeric molecule is sufficiently high to allow for isolation of the individual conformers. Whereby, atropisomeric pharmaceutical ingredients can differ in their pharmacokinetic and selectivity properties towards a hitting target (Fig. 3). [177][178][179][180][181][182][183]   Treatment of heart failure with a combination of valsartan Neprilysin inhibitor 186,187 Antihypertensive Since inhibition of angiotensin II type 1 (AT1) receptor reduces chronic inammation associated with hypertension, we evaluated the anti-inammatory potential and the underlying mechanism of masartan 188 Anti-inammatory 188

Antiviral
As a result of sp 2 hybridization of CNTs between the drug and target protein sequence, leads to improving the uorescence reactivity. Because the conjugated system of biphenyl and the presence of Cs/CNT can increase the electroactive surface area of the electrode, leading to an increase in the number of structural aws 189 Treatment selections for hepatitis C virus 189,190  Active for the AT1 receptor [191][192][193] Lung-selective muscarinic cholinergic receptor (mAChR) antagonist Biphenyl moiety enhances longlasting and potency of mediated antagonism of mAChR-causing contraction of human bronchial tissues 194 Nebulized inhalation solution to produce long-acting bronchodilation 194 Microsomal triglyceride transfer protein inhibitor Biphenyl scaffold for nesting Treatment for human dyslipidemias 195 Anti-human neutrophil collagenase (MMP-8) 196 Biphenyl residues hit the active site close the catalytic zinc ion that would consequently inhibit the collagenase activity 196 b 3 -Adrenergic receptor agonist RHS of biphenyl ring affords potent human b3-AR agonists with a chlorophenyl ring on the LHS side 197 Evokes bladder relaxation Overactive urinary bladder Increases micturition reex threshold in the dogs [197][198][199] Analysis of water mediated binding in the context of a DNA complex The interactions of the molecules containing of biphenyl with DNA AT sites increasing DNase I footprinting depending on increasing conjugation process which enhancing biosensorsurface plasmon resonance, circular dichroism microcalorimetry, and isothermal titration 200 Promising agent against parasites Change in AT sequences with destruction of the kinetoplast and cell death 200 Antiprotozoal Biphenyl scaffold for nesting Anti-trypanosomal 201

Conclusion
With the continuously increasing importance of biphenyl scaffolds as the structurally decisive scaffolds in bioactive natural products and pharmaceuticals drugs, formidable efforts have been carried out to summarize gradual developments of biphenyl compounds and their isosteres via metallic catalyzed reaction which covered the literature reported in the last decades based on this thrilling area of research. In this review several chemical reactions of biphenyl with different reagents have been discussed. The profound discussion of different captivating mechanisms associated with the role of numerous key catalysts and reagents through this review is believed to be benecial for the synthetic community to apply these methods for practical purposes. Additionally, the efficacy of biphenyl compounds in medicinal chemistry and academic industry has been covered, and thereby will be helpful for future research. Although, obtaining these frameworks with particular substitution patterns is still an intimidating exercise. Atropisomerization phenomena of biphenyl derivatives also has taken into account Therefore, we believe that this review can be a guiding principle for synthetic and medicinal chemists working in this eld.

Conflicts of interest
The authors conrm that this article content has no conict of interest.